Dreyer Jakob K, Vander Weele Caitlin M, Lovic Vedran, Aragona Brandon J
Department of Neuroscience and Pharmacology, University of Copenhagen, DK-2200 Copenhagen, Denmark,
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
J Neurosci. 2016 Jan 6;36(1):98-112. doi: 10.1523/JNEUROSCI.2326-15.2016.
Dynamic signaling of mesolimbic dopamine (DA) neurons has been implicated in reward learning, drug abuse, and motivation. However, this system is complex because firing patterns of these neurons are heterogeneous; subpopulations receive distinct synaptic inputs, and project to anatomically and functionally distinct downstream targets, including the nucleus accumbens (NAc) shell and core. The functional roles of these cell populations and their real-time signaling properties in freely moving animals are unknown. Resolving the real-time DA signal requires simultaneous knowledge of the synchronized activity of DA cell subpopulations and assessment of the down-stream functional effect of DA release. Because this is not yet possible solely by experimentation in vivo, we combine computational modeling and fast-scan cyclic voltammetry data to reconstruct the functionally relevant DA signal in DA neuron subpopulations projecting to the NAc core and shell in freely moving rats. The approach provides a novel perspective on real-time DA neuron firing and concurrent activation of presynaptic autoreceptors and postsynaptic targets. We first show that individual differences in DA release arise from differences in autoreceptor feedback. The model predicts that extracellular DA concentrations in NAc core result from constant baseline DA firing, whereas DA concentrations in NAc shell reflect highly dynamic firing patters, including synchronized burst firing and pauses. Our models also predict that this anatomical difference in DA signaling is exaggerated by intravenous infusion of cocaine.
Orchestrated signaling from mesolimbic dopamine (DA) neurons is important for initiating appropriate behavior in response to salient stimuli. Thus, subpopulations of mesolimbic DA neurons show different in vitro properties and synaptic inputs depending on their specific projections to the core and shell subterritories of the nucleus accumbens (NAc). However, the functional consequence of these differences is unknown. Here we analyze and model DA dynamics in different areas of the NAc to establish the real-time DA signal. In freely behaving animals, we find that the DA signal from mesencephalic neurons projecting to the NAc shell is dominated by synchronized bursts and pauses, whereas signaling is uniform for core-projecting neurons; this difference is amplified by cocaine.
中脑边缘多巴胺（DA）神经元的动态信号传导与奖励学习、药物滥用和动机有关。然而，该系统很复杂，因为这些神经元的放电模式是异质性的；亚群接受不同的突触输入，并投射到解剖学和功能上不同的下游靶点，包括伏隔核（NAc）壳和核心。这些细胞群的功能作用及其在自由活动动物中的实时信号特性尚不清楚。解析实时DA信号需要同时了解DA细胞亚群的同步活动，并评估DA释放的下游功能效应。由于仅通过体内实验尚无法做到这一点，我们结合计算模型和快速扫描循环伏安法数据，以重建自由活动大鼠中投射到NAc核心和壳的DA神经元亚群中功能相关的DA信号。该方法为实时DA神经元放电以及突触前自身受体和突触后靶点的同时激活提供了新的视角。我们首先表明，DA释放的个体差异源于自身受体反馈的差异。该模型预测，NAc核心中的细胞外DA浓度源于持续的基线DA放电，而NAc壳中的DA浓度反映了高度动态的放电模式，包括同步爆发放电和暂停。我们的模型还预测，静脉注射可卡因会加剧DA信号传导的这种解剖学差异。
中脑边缘多巴胺（DA）神经元的精心编排的信号传导对于响应显著刺激启动适当行为很重要。因此，中脑边缘DA神经元亚群根据其向伏隔核（NAc）核心和壳亚区域的特定投射表现出不同的体外特性和突触输入。然而，这些差异的功能后果尚不清楚。在这里，我们分析并模拟了NAc不同区域的DA动态，以建立实时DA信号。在自由行为的动物中，我们发现投射到NAc壳的中脑神经元的DA信号以同步爆发和暂停为主，而投射到核心的神经元的信号是均匀的；这种差异会被可卡因放大。
